biology, histones are the chief proteincomponents of chromatin. They act as spools around which DNAwinds, and they play a role in gene regulation. Without histones, the unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA, but wound on the histones it has about 90 millimeters of chromatin, which, when duplicated and condensed during mitosis, result in about 120 micrometers of chromosomes. [ Redona C, Pilcha D, Rogakoub E, Sedelnikovaa O, Newrocka K, Bonnera W. " [http://www.ncbi.nlm.nih.gov/pubmed/11893489?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Histone H2A variants H2AX and H2AZ] ." "Current Opinion in Genetics & Development" 2002 Apr 1; 12(2): 162-169. PMID 11893489]
Two each of the class H2A, H2B, H3 and H4, so-called "core histones", assemble to form one octameric
nucleosomecore particle by wrapping 146 base pairsof DNA around the protein spool in 1.65 left-handed super-helical turncite journal |author=Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ |title=Crystal structure of the nucleosome core particle at 2.8 A resolution |journal=Nature |volume=389 |issue=6648 |pages=251–60 |year=1997 |pmid=9305837 |doi=10.1038/38444 [http://www.pdb.org/pdb/explore.do?structureId=1AOI PDB entry 1AOI] ] . The linker histone H1 binds the nucleosome and the entry and exit sites of the DNA, thus locking the DNA into place [(Daniel H. Farkas. Histone.In: DNA Simplified. THe Hitchhiker's Guide to DNA. AACC Press .Washington, D.C.) 0-915274-84-1] and allowing the formation of higher order structure. The most basic such formation is the 10 nm fiber or beads on a string conformation. This involves the wrapping of DNA around nucleosomes with approximately 50 base pairs of DNAspaced between each nucleosome(also referred to as linker DNA). The assembled histones and DNAis called chromatin. Higher order structures include the 30 nm fiber (forming an irregular zigzag) and 100 nm fiber, these being the structures found in normal cells. During mitosis and meiosis, the condensed chromosomes are assembled through interactions between nucleosomes and other regulatory proteins.
nucleosomecore is formed of two H2A-H2B dimersand a H3-H4 tetramer, forming two nearly symmetrical halves by tertiary structure(C2 symmetry; one macromoleculeis the mirror image of the other). The H2A-H2B dimers and H3-H4 tetramer also show pseudodyad symmetry. The 4 'core' histones (H2A, H2B, H3 and H4) are relatively similar in structure and are highly conserved through evolution, all featuring a 'helix turn helix turn helix' motif (which allows the easy dimerisation). They also share the feature of long 'tails' on one end of the amino acidstructure - this being the location of post-transcriptional modification (see below).
In all, histones make five types of interactions with DNA:
# Helix-dipoles from alpha-helices in H2B, H3, and H4 cause a net positive charge to accumulate at the point of interaction with negatively charged
phosphategroups on DNA.
Hydrogen bondsbetween the DNA backbone and the amide group on the main chain of histone proteins.
# Nonpolar interactions between the histone and
deoxyribosesugars on DNA.
# Salt links and hydrogen bonds between side chains of basic amino acids (especially
lysineand arginine) and phosphate oxygens on DNA.
# Non-specific minor groove insertions of the H3 and H2B N-terminal tails into two minor grooves each on the DNA molecule.
The highly basic nature of histones, aside from facilitating DNA-histone interactions, contributes to the water solubility of histones.fact|date=July 2007
Histones are subject to posttranslational modification by enzymes primarily on their N-terminal tails, but also in their globular domainsfact|date=July 2007. Such modifications include
methylation, citrullination, acetylation, phosphorylation, Sumoylation, ubiquitination, and ADP-ribosylation. This affects their function of gene regulation (see functions).
genes that are active have less bound histone, while inactive genes are highly associated with histones during interphasefact|date=July 2007. It also appears that the structure of histones has been evolutionarily conserved, as any deleterious mutationswould be severely maladaptive.
Compacting DNA Strands
Histones act as spools around which DNA winds. This enables the compaction necessary to fit the large
genomes of eukaryotes inside cell nuclei: the compacted molecule is 30,000 times shorter than an unpacked molecule.
Histone modifications in
posttranslational modifications which alter their interaction with DNAand nuclear proteins. The H3 and H4 histones have long tails protruding from the nucleosome which can be covalently modified at several places. Modifications of the tail include methylation, acetylation, phosphorylation, ubiquitination, sumoylation, citrullination, and ADP-ribosylation. The core of the histones (H2A and H3) can also be modified. Combinations of modifications are thought to constitute a code, the so-called " histone code"cite journal |author=Strahl BD, Allis CD |title=The language of covalent histone modifications |journal=Nature |volume=403 |issue=6765 |pages=41–5 |date= 6 January 2000|pmid=10638745 |doi=10.1038/47412] cite journal |author=Jenuwein T, Allis CD |title=Translating the histone code |journal=Science |volume=293 |issue=5532 |pages=1074–80 |date= 10 August 2001|pmid=11498575 |doi=10.1126/science.1063127] . Histone modifications act in diverse biological processes such as gene regulation, DNA repairand chromosome condensation ( mitosis).fact|date=July 2007
The common nomenclature of histone modifications is as follows:
#The name of the histone ("e.g" H3)
#The single letter
amino acidabbreviation ("e.g." K for Lysine) and the amino acid position in the protein
#The type of modification (Me:
methyl, P: phosphate, Ac: acetyl, Ub: ubiquitin)
So H3K4me1 denotes the monomethylation of the 4th residue (a lysine) from the start (i.e., the
N-terminal) of the H3 protein.
For a detailed example of histone modifications in transcription regulation see RNA polymerase control by chromatin structure and table.
Influence on gene expression in mammalian cells:
Histones were discovered in 1884 by
Albrecht Kossel. The word "histone" dates from the late 19th century and is from the German "Histon", of uncertain origin: perhaps from Greek "histanai" or from "histos". Until the early 1990s, histones were dismissed as merely packing material for nuclear DNA. During the early 1990s, the regulatory functions of histones were discoveredfact|date=July 2007.
Conservation across species
Histones are found in the nuclei of eukaryotic cells, and in certain
Archaea, namely Euryarchaea, but not in bacteria. Archaeal histones may well resemble the evolutionary precursors to eukaryotic histones. Histone proteins are among the most highly conserved proteins in eukaryotes, emphasizing their important role in the biology of the nucleus.fact|date=July 2007
Core histones are highly conserved proteins, that is, there are very few differences among the amino acid sequences of the histone proteins of different species. Linker histone usually has more than one form within a species and is also less conserved than the core histones.fact|date=July 2007
There are some "variant" forms in some of the major classes. They share amino acid sequence homology and core structural similarity to a specific class of major histones but also have their own feature that is distinct from the major histones. These "minor histones" usually carry out specific functions of the chromatin metabolism. For example, histone H3-like CenpA is a histone only associated with
centromereregion of the chromosome. Histone H2A variant H2A.Z is associated with the promoters of actively transcribed genes and also involved in the formation of the heterochromatin. Another H2A variant H2A.X binds to the DNA with double strand breaks and marks the region undergoing DNA repair. Histone H3.3 is associated with the body of actively transcribed genes.fact|date=July 2007
* [http://www.nextbio.com/b/home/home.nb?q=histone#tab=lit Nextbio]
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